Neuroligin-Neurexin Interaction: Difference between revisions
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The <scene name='Neuroligin-Neurexin_Interaction/Neuroligin_dimer_opening/1'>extracellular residues of NLGNs</scene>, which bind to the LNS domains of both alpha and beta NRXNs with nanomolar affinity, are <scene name='Neuroligin-Neurexin_Interaction/Neuroligin_opening/1'>composed of a single domain</scene> that is homologous with [[acetylcholinesterase]] (AChE).<ref name="Sudhof"/> Neuroligin-4 consists of a twisted <scene name='Neuroligin-Neurexin_Interaction/Neuroligin_helices_and_sheets/3'>12 stranded beta sheet surrounded by 14 alpha helices</scene>. Three intramolecular <scene name='Neuroligin-Neurexin_Interaction/Neuroligin_disulfide/1'>disulfide bridges</scene> between residues Cys110-Cys146, Cys306-Cys317, and Cys476-Cys510, stabilize the structure. Neuroligins readily <scene name='Neuroligin-Neurexin_Interaction/Dimer/1'>form a dimmer</scene> consisting of two neuroligin subunits. 100% of the dimer <scene name='Neuroligin-Neurexin_Interaction/Hydrophobic_interactions/1'>interactions are hydrophobic</scene> with the most unique feature being a <scene name='Neuroligin-Neurexin_Interaction/4_helix_bundle/2'>prominent four-helix bundle</scene>.<ref name="Fabrichny"/> The <scene name='Neuroligin-Neurexin_Interaction/Central_pocket/1'>central pocket within Neuroligin</scene>, which in Acetylcholinesterase contains the active center and oxyanion hole, is catalytically inactive due to a substitution of Gly for Ser <scene name='Neuroligin-Neurexin_Interaction/Central_pocket_gly/1'>at position 254</scene>, which is typically part of AChE’s hydrolytic catalytic triad. The <scene name='Neuroligin-Neurexin_Interaction/Cys_loop/3'>so-called Cys-Loop</scene> (Residues Cys110-Cys146) forms one side of the rim of the central pocket and is a homolog of the lid found in [[Lipase|lipases]] of the α/β-hydrolase fold family. This Cys-Loop blocks the entry of substrate to the central pocket and provides stability to the NLGN structure.<ref name="Fabrichny"/> | The <scene name='Neuroligin-Neurexin_Interaction/Neuroligin_dimer_opening/1'>extracellular residues of NLGNs</scene>, which bind to the LNS domains of both alpha and beta NRXNs with nanomolar affinity, are <scene name='Neuroligin-Neurexin_Interaction/Neuroligin_opening/1'>composed of a single domain</scene> that is homologous with [[acetylcholinesterase]] (AChE).<ref name="Sudhof"/> Neuroligin-4 consists of a twisted <scene name='Neuroligin-Neurexin_Interaction/Neuroligin_helices_and_sheets/3'>12 stranded beta sheet surrounded by 14 alpha helices</scene>. Three intramolecular <scene name='Neuroligin-Neurexin_Interaction/Neuroligin_disulfide/1'>disulfide bridges</scene> between residues Cys110-Cys146, Cys306-Cys317, and Cys476-Cys510, stabilize the structure. Neuroligins readily <scene name='Neuroligin-Neurexin_Interaction/Dimer/1'>form a dimmer</scene> consisting of two neuroligin subunits. 100% of the dimer <scene name='Neuroligin-Neurexin_Interaction/Hydrophobic_interactions/1'>interactions are hydrophobic</scene> with the most unique feature being a <scene name='Neuroligin-Neurexin_Interaction/4_helix_bundle/2'>prominent four-helix bundle</scene>.<ref name="Fabrichny"/> The <scene name='Neuroligin-Neurexin_Interaction/Central_pocket/1'>central pocket within Neuroligin</scene>, which in Acetylcholinesterase contains the active center and oxyanion hole, is catalytically inactive due to a substitution of Gly for Ser <scene name='Neuroligin-Neurexin_Interaction/Central_pocket_gly/1'>at position 254</scene>, which is typically part of AChE’s hydrolytic catalytic triad. The <scene name='Neuroligin-Neurexin_Interaction/Cys_loop/3'>so-called Cys-Loop</scene> (Residues Cys110-Cys146) forms one side of the rim of the central pocket and is a homolog of the lid found in [[Lipase|lipases]] of the α/β-hydrolase fold family. This Cys-Loop blocks the entry of substrate to the central pocket and provides stability to the NLGN structure.<ref name="Fabrichny"/> | ||
<scene name='Neuroligin-Neurexin_Interaction/Combo/3'>NRXN-beta-1 is bound</scene> through its <scene name='Neuroligin-Neurexin_Interaction/Combo_hyper/1'>hypervariable loop edge</scene> to the <scene name='Neuroligin-Neurexin_Interaction/Combo_electro/2'>electronegative surface</scene> of the NLGN-4 molecule, opposite the Cys-loop. The NRXN-NLGN interface is established by both indirect and direct interactions. Indirect interactions include **coordination of a divalent calcium cation** by residues Asp 137, Asn 238, Val 154 and Ile 236 of NRXN-Beta1 and residues Gln 359 and Gly 360 of NLGN-4. Direct interactions between NRXN and NLGN include extensive hydrogen bonding and Van der Waals contacts as well as salt bridges between residues NRXN-Arg 109 & NLGN-Glu 270 and NRXN-Arg232 & NLGN Asp 351. The vast majority of these interactions are conserved among all neuroligin types.<ref name="Fabrichny"/> | <scene name='Neuroligin-Neurexin_Interaction/Combo/3'>NRXN-beta-1 is bound</scene> through its <scene name='Neuroligin-Neurexin_Interaction/Combo_hyper/1'>hypervariable loop edge</scene> to the <scene name='Neuroligin-Neurexin_Interaction/Combo_electro/2'>electronegative surface</scene> of the NLGN-4 molecule, <scene name='Neuroligin-Neurexin_Interaction/Combo_total/1'>opposite the Cys-loop</scene>. The NRXN-NLGN interface is established by both indirect and direct interactions. Indirect interactions include **coordination of a divalent calcium cation** by residues Asp 137, Asn 238, Val 154 and Ile 236 of NRXN-Beta1 and residues Gln 359 and Gly 360 of NLGN-4. Direct interactions between NRXN and NLGN include extensive hydrogen bonding and Van der Waals contacts as well as salt bridges between residues NRXN-Arg 109 & NLGN-Glu 270 and NRXN-Arg232 & NLGN Asp 351. The vast majority of these interactions are conserved among all neuroligin types.<ref name="Fabrichny"/> | ||
Several **point mutations** (R437C (451 in NLGN 3), G99S, K378R, & V403M) within NLGN have been positively linked with Autism Spectrum Disorders. Although these mutations are remote from the NLGN-NRXN interface, conclusions can be drawn as to their impact on the function of NLGN. **Arg437Cys**, a mutation shown to result in “savant” like attributes in mice, is believed to increase retention of NLGN in the endoplasmic reticulum preventing correct positioning at the cell surface. It could also disrupt a dense network of charged residues (Asp 388, Asp 486, Glu 434, and Lys 338) through Trp 484, which are believed to be important for processing events. **Val403Met** is believed to affect correct folding of the C-terminal domain of NLGN and prevent formation of the functional dimer. **The Lys378Arg mutation** which interacts with the Cys-loop Asp 122 through Van der Waals contacts could disrupt the Cys-loop reducing NLGN structural integrity. These mutations do not entirely disrupt NLGNs interaction with NRXN, but do impact NLGN in the subtle ways from which Autism likely arises.<ref name="Fabrichny"/> | Several **point mutations** (R437C (451 in NLGN 3), G99S, K378R, & V403M) within NLGN have been positively linked with Autism Spectrum Disorders. Although these mutations are remote from the NLGN-NRXN interface, conclusions can be drawn as to their impact on the function of NLGN. **Arg437Cys**, a mutation shown to result in “savant” like attributes in mice, is believed to increase retention of NLGN in the endoplasmic reticulum preventing correct positioning at the cell surface. It could also disrupt a dense network of charged residues (Asp 388, Asp 486, Glu 434, and Lys 338) through Trp 484, which are believed to be important for processing events. **Val403Met** is believed to affect correct folding of the C-terminal domain of NLGN and prevent formation of the functional dimer. **The Lys378Arg mutation** which interacts with the Cys-loop Asp 122 through Van der Waals contacts could disrupt the Cys-loop reducing NLGN structural integrity. These mutations do not entirely disrupt NLGNs interaction with NRXN, but do impact NLGN in the subtle ways from which Autism likely arises.<ref name="Fabrichny"/> | ||